Tauopathies have in common the accumulation of insoluble, hyperphosphorylated tau protein in the brain. More than 20 different neurodegenerative disorders are characterized by some degree of neurofibrillary degeneration and can be classified as tauopathies (Williams 2006). Prototypical tauopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are characterized by tau inclusions being the sole or predominant central nervous system lesions. Prototypical tauopathies differ from other tauopathies where tau aggregates are found in the presence of other neuropathological features, like the amyloid beta (Aβ) plaques found in Alzheimer's disease (AD) or the Lewy bodies found in Parkinson's disease (PD). In these non-prototypical tauopathies, it is more uncertain if the tau pathology represents the primary disease driver or if it is secondary to other protein misfolding and neurodegeneration.
Progressive supranuclear palsy (PSP, also known as Steele-Richardson-Olszewski syndrome) is a progressive neurodegenerative disorder, with an estimated annual incidence of 5-7 per 100,000 (Golbe 2014). Within the US, the disease affects approximately 20,000 individuals. There is no apparent geographical, ethnic, gender, or racial disparity in PSP frequency. PSP can initially present with clinical symptoms similar to other brain disorders, including idiopathic Parkinson's disease. For this reason, correct diagnosis of PSP is sometimes delayed, usually taking place 1 to 3 years after the initial onset of clinical symptoms. Symptom onset is most often between the ages of 50 to 70 years and although the clinical course is variable, the typical survival from time of symptom onset is 5 to 9 years (Houghton, 2007). Though heterogeneity in clinical presentation exists, the most common and initially described PSP syndrome, now referred to as Richardson's Syndrome, are the presence of prominent postural instability and axial rigidity leading to falls, supranuclear gaze palsy causing range of vision impairment, frontal-subcortical dementia, and dysphagia leading to aspiration. The course of disease is progressive and uniformly fatal (Williams and Lees 2009).
Pathologically, PSP is characterized by the abnormal accumulation of hyper phosphorylated, insoluble aggregates of tau protein in neurons and glia in the brainstem, cerebellum, basal ganglia, and cerebral cortex (Williams and Lees 2009). The degree and distribution of tau aggregation in PSP is strongly correlated with PSP symptomatology during life (Schofield et al. 2012). The National Institute of Neurological Disorders and the Society for Progressive Supranuclear Palsy (NINDS-SPSP) research criteria which describe Richardson's Syndrome are highly predictive of underlying PSP pathology (Litvan et al. 1996). Neuronal loss in various regions of the brain accompanies neurofibrillary tangles (NFTs) that are composed of tau aggregates. Multiple neurotransmitter abnormalities arise as well, including those affecting specific dopaminergic, cholinergic, GABAergic, and noradrenergic systems.
There are no currently approved treatments for PSP (Stamelou et al. 2010). The negative outcomes of therapeutic efficacy studies in PSP preclude recommending an evidence-based standard therapy (Boxer et al. 2014). In the absence of any effective disease modifying or neuroprotective therapies, PSP represents an urgent unmet medical need.
Alzheimer's disease (AD) is a common chronic progressive neurodegenerative disease in which there is an irreversible loss of cognitive and behavioral functions. The disease can persevere for over 10 years, advancing from mild symptoms to extremely severe manifestations. AD is said to afflict approximately 10% of the population over the age of 65 and more than 30% of the population over the age of 80. Alzheimer's disease presents itself pathologically as extracellular amyloid plaques and intracellular neurofibrillary tangles. The neurofibrillary tangles are composed, e.g., of the microtubule-binding protein tau, which is assembled into paired helical and straight filaments. It has been suggested that these entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly, or vice versa, is not clear.
The intracellular neurofibrillary structures of tauopathies (neurofibrillary tangles, dystrophic neurites, and neurophil threads) have paired helical filaments (PHFs). The major protein subunit of the PHFs is microtubule associated protein tau in abnormally hyperphosphorylated form. Neurons with neurofibrillary changes degenerate, and the degree of this degeneration directly correlates with the degree of dementia in the affected individuals.
Other tauopathies known to have filamentous cellular inclusions containing microtubule associated protein tau include Pick's disease (PiD), a group of related disorders collectively termed frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), amyotropic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), dementia pugilistica (DP), Gerstmann-Straussler-Scheinker disease (GSSD), Lewy body disease, chronic traumatic encephalopathy (CTE), and Huntington disease. Although the etiology, clinical symptoms, pathologic findings and the biochemical composition of filamentous cellular inclusions in these diseases are different, there is emerging evidence suggesting that the mechanisms involved in aggregation of normal cellular proteins to form various filamentous inclusions being comparable. It is believed, that an initial alteration in conformation of microtubule associated protein tau, acts to initiate the generation of nuclei or seeds for filament assembly, is one of the key features. This process can be influenced by the posttranslational modification of normal proteins, by mutation or deletion of certain genes and by factors that bind normal proteins and thus alter their conformation.